Methods of alleviating convulsions and pain employing 4-aryloxy-1,2,3,4 tetrahydroisoquinolines

ABSTRACT

This invention relates to 4-aryloxy-1,2,3,4-tetrahydroisoquinolines of the formula ##STR1## where Y is hydrogen and alkoxy; X is hydrogen, cyano, benzoyl, trifluoromethyl, phenyl, halogen, alkyl alkoxy and nitro; R is hydrogen and alkyl; R 1  is hydrogen, alkyl, aralkyl, ##STR2## and CO 2  R 4  where R 1  is aryl and alkyl; R 2  and R 3  are the same or differnt and are hydrogen and alkyl or R 2  and R 3  are fused together to form a pyrrolidino or a piperidino ring substituent; and m is an integer of 1 or 2; n is an integer of 2 or 3; and a pharmaceutically acceptable acid addition salt thereof.

This is a division of application Ser. No. 451,139 filed Dec. 20, 1982,now U.S. Pat No. 4,477,670, which is a division of Ser. No. 235,801,filed Feb. 19, 1981, now U.S. Pat. No. 4,375,471.

The compounds of the invention have the general formula ##STR3## where Yis hydrogen and alkoxy; X is hydrogen, cyano, benzoyl, trifluoromethyl,phenyl, halogen, alkyl alkoxy and nitro; R is hydrogen and alkyl; R₁ ishydrogen, alkyl, aralkyl, ##STR4## and CO₂ R₄ where R₄ is aryl andalkyl; R₂ and R₃ are the same or different and are hydrogen and alkyl orR₂ and R₃ are fused together to form a pyrrolidino or a piperidino ringsubstituent; m is an integer of 1 or 2; n is an integer of 2 or 3; and apharmaceutically acceptable acid addition salt thereof.

To the best of our knowledge, the compounds of the present inventionhave not heretofore been described or suggested.

In the above definitions and as used hereinafter, the terms "alkyl," and"alkoxy" mean the group it is describing contains 1 to 6 carbon atoms.The term "alkyl" refers to a straight or branched chain hydrocarboncontaining no unsaturation. The term "alkoxy" refers to a monovalentsubstituent which consists of an alkyl group linked through an etheroxygen having its free valence bond from the ether oxygen. The termaralkyl refers to a straight or branched chain hydrocarbon of 1 to 6carbon atoms containing no unsaturation in which an alkyl carbon atom issubstituted by an aryl and having its free valence bond from the alkyllinkage. The term "halogen" refers to a member of the family consistingof fluorine, chlorine, bromine and iodine.

The compounds of the present invention are prepared in the followingmanner. The substituents Y, X, R, R₁, R₂ and R₃ and the members m and nare as defined earlier, unless indicated otherwise. A substituted1,2,3,4-tetrahydro-4-isoquinolinol of the formula ##STR5## where R ishydrogen and R₁ is hydrogen, alkyl or aralkyl or a salt thereof isreacted with a substituted phenyl compound II of the formula ##STR6##where X is as defined above and where Z is halogen, such as fluorine toform a compound of the invention ##STR7## where R₁ is alkyl, e.g.,methyl.

Compound I is generally conventionally prepared in the manner describedby G. Grethe, et al, in the Journal of Organic Chemistry, Vol. 33, 494(1968) which is incorporated hereinto by reference. Compound I where Yis hydrogen may be prepared in the manner described by I. G. Hinton etal, J. Chemical Society 599 (1959). Compound I where Y is methoxy may beprepared in the manner described by B. Umerzawa et al, Chem. Pharm.Bull. 19, 2138 (1971).

Typically, a salt of Compound I is first formed, in a conventionalmanner, as for example by reacting Compound I with sodium hydride at atemperature of 50° to 80° C. for 1 to 5 hours. The salt is then in turnreacted with Compound II, typically at a temperature of (10°-135° C.)for 5 to 20 hours to form Compound III of the invention.

Alternatively, where it is desired to have a compound of the inventionwhere R is alkyl an isoquinoline is selected of the formula ##STR8##where R₁ is alkyl, e.g., methyl or aralkyl, e.g., benzyl. Compound IV isreacted under conventional conditions, e.g., 5° to 25° C., for 1 to 5hours, with a Grignard reagent R--Mg Z', where R is alkyl of 1 to 6carbon atoms, in a solvent such as ethyl ether, or THF, and Z' is ahalogen, to form an alkyl substituted isoquinolinol of the formula##STR9## where, R is alkyl and R₁ is alkyl or aralkyl. Alternatively,Compound IV can be reacted with an organometallic other than theGrignard reagent to form the isoquinolinol V. Typically organometallicssuch as organolithium, organopotassium or organosodium compounds can beused, in a well known, conventional manner, instead of the Grignardreagent.

Compound V or a salt thereof is then reacted with Compound II, asdescribed above, to form a Compound VI of the invention ##STR10## whereR is alkyl and R₁ is alkyl or aralkyl.

Compounds III or VI of the invention where R₁ is alkyl or aralkyl areconverted to their corresponding compounds of the invention where R₁ isCOOR₄, where R₄ is alkyl of 1 to 6 carbon atoms and ##STR11## byreaction with a haloalkanoate having a formula ##STR12## where Z" ishalogen, to form Compound VII, an intermediate compound of the inventionhaving the formula ##STR13## where X, Y, R and R₄ are as originallydefined. Where Compound III or VI is employed with R₁ being alkyl, thereaction is typically carried out at 25° to 120° C. in a solvent such asbenzene or toluene in the presence of a base, such as K₂ CO₃, Na₂ CO₃,or NaHCO₃, for 1 to 20 hours. Where Compound III or VI is employed withR₁ being aralkyl, the reaction with the haloalkanoate ##STR14## istypically carried out at 5° to 110° C. in a solvent such as chloroform,toluene or dichloromethane, in the presence of a base, such astriethylamine, for 5 to 20 hours.

Compound VII can be hydrolyzed, in a conventional manner, under basicconditions, to form Compound VIII of the invention where R₁ is hydrogen.##STR15## Typically, the hydrolysis is carried out in an aqueousalcoholic solution of a base, e.g. KOH, at a temperature of 80° to 120°C. for 5 to 20 hours.

Compound VIII, is reacted with a haloalkylamine of the formula ##STR16##where Z'" is halogen, to form a compound of the invention having theformula ##STR17## Typically, the reaction is carried out in the presenceof a base, e.g., K₂ CO₃, and an iodide, e.g., KI, with a solvent, suchas butanol, at a temperature of 50° to 120° C. for 5 to 20 hours.

The compounds of the invention are primarily useful as analgesic andanticonvulsant agents. The compounds of the invention are useful asanalgesic agents due to their ability to alleviate pain in mammals whichis demonstrated in the phenyl-para-quinone writhing assay in mice, astandard assay for analgesia [Proc. Soc. Exptl. Biol. Med., 95, 729(1953)]. Listed below in Table III is the analgesic effect of some ofthe compounds of the invention, expressed as percent inhibition ofphenyl-para-quinone induced writhing.

                  TABLE III                                                       ______________________________________                                                               Dose                                                                          (Subcut-                                                                      aneous)  % Inhib-                                      Compound               (mg/kg)  ition                                         ______________________________________                                        1,2,3,4-tetrahydro-4-(p-trifluoro-                                                                   25.0     51                                            methylphenyl)isoquinoline hydro-                                              chloride                                                                      2-(3-dimethylaminopropyl)-1,2,3,4-                                                                   25.0     53                                            tetrahydro-4-(m-trifluoromethyl                                               phenoxy)isoquinoline dimaleate                                                2-(2-N,N--dimethylaminoethyl)-                                                                       14.4     50                                            1,2,3,4-tetrahydro-4-(p-trifluoro-                                            methylphenoxy)isoquinoline dihydro-                                           chloride                                                                      2-(2-N,N--diethylaminoethyl)-1,2,3,4-                                                                21.8     50                                            tetrahydro-4-(p-trifluoromethylphenoxy)                                       isoquinoline dioxalate                                                        2-(3-piperidinopropyl)-1,2,3,4-tetrahydro-                                                           15.4     50                                            4-(p-trifluoromethylphenoxy)isoquinoline                                      dioxalate                                                                     4-(p-nitrophenoxy)-1,2,3,4-tetrahydroiso-                                                            25.0     65                                            quinoline maleate                                                             2-(3-N,N--dimethylaminopropyl)-4-(p-nitro-                                                           14.7     50                                            phenoxy)-1,2,3,4-tetrahydroisoquinoline                                       dihydrochloride                                                               Propoxyphene (standard)                                                                               3.9     50                                            ______________________________________                                    

The analgesic effect is achieved when the compounds of the invention areadministered to a subject requiring such treatment at an effective oral,parenteral or intravenous dose of from 1 to 100 mg/kg of body weight perday. A preferred effective dose within this range is from about 15 to 50mg/kg of body weight per day.

The compounds of the present invention are also useful as anticonvulsantagents for mammals are evidenced by the supra maximal electroshock assayof Woodbury, L. A. and Davenport, U. D. in Arch. Int. Pharmacodynam,Vol. 92 (1952) at pages 97-107.

In this method, groups of male mice are used (Charles River, CD-1),18-30 grams. Drugs are prepared using distilled water and if insoluble,a surfactant is added. Control animals receive vehicle. Drugs areroutinely administered intraperitoneally. The route of administrationmay be varied (orally, subcutaneously). The dosage volume is 10 ml/kg.

The animal's eyes are placed across the output terminals of an A.C.shocker that delivers 205 volts rms for 300 milliseconds. Electrodepaste coats the animal's eyes at the point of contact with theterminals.

A compound is considered to give protection if the mouse does notexhibit extensor tonus. Protection is expressed as normalized percentinhibition relative to vehicle control.

A time response is carried out using 6 animals per group. Animals aretested at 30, 60 and 120 minutes post-drug. Additional time periods aretested if indicated by previous tests.

Listed below in Table II is the anticonvulsant effect of some of thecompounds of the invention expressed as percent inhibition.

                  TABLE II                                                        ______________________________________                                                              Dose                                                                          (Intraper-                                                                    itoneal)  % Inhib-                                      Compound              (mg/kg)   ition                                         ______________________________________                                        2-methyl-1,2,3,4-tetrahydro-4-                                                                      50.0      50                                            (p-trifluoromethylphenoxy)                                                    isoquinoline oxalate                                                          1,2,3,4-tetrahydro-4- 35.0      50                                            (p-trifluoromethyl-                                                           phenoxy)isoquinoline                                                          hydrochloride                                                                 2-(3-dimethylaminopropyl)-                                                                          14.4      50                                            1,2,3,4-tetrahydro-4-(p-tri-                                                  fluoromethylphenoxy)iso-                                                      quinoline dihydrochloride                                                     2-methyl-1,2,3,4-tetrahydro-                                                                        50.0      67                                            4-(m-trifluoromethylphenoxy)-                                                 isoquinoline maleate                                                          4-(p-chlorophenoxy)-1,2,3,4-                                                                        23.4      50                                            tetrahydroisoquinoline hydro-                                                 chloride                                                                      1,2,3,4-tetrahydro-4-(m-trifluoro-                                                                  21.0      50                                            methylphenoxy)isoquinoline maleate                                            2-(3-dimethylaminopropyl)-1,2,3,4-                                                                  50.0      100                                           tetrahydro-4-(m-trifluoromethyl                                               phenoxy)isoquinoline dimaleate                                                4-(p-chlorophenoxy)-2-(3-dimethyl-                                                                  50.0      100                                           aminopropyl)-1,2,3,4-tetrahydroiso-                                           quinoline dimaleate                                                           2-(2-N,N--dimethylaminoethyl-1,2,3,4-                                                               10.3      50                                            tetrahydro-4-(p-trifluoromethylphenoxy)                                       isoquinoline dihydrochloride                                                  2-(2-N,N--diethylaminoethyl)-1,2,3,4-                                                               14.8      50                                            tetrahydro-4-(p-trifluoromethylphenoxy)-                                      isoquinoline dioxalate                                                        Chlorodiazepoxide (standard)                                                                         8.0      50                                            Diazepam (standard)    1.7      50                                            ______________________________________                                    

The anticonvulsant effect is achieved when the compounds of theinvention are administered to a subject requiring such treatment at aneffective oral, parenteral or intravenous dose of from 10 to 100 mg/kgof body weight per day. A preferred effective dose within this range isfrom about 20 to 50 mg/kg of body weight per day.

Additionally, selected compounds of the present invention exhibit someantidepressant, and diuretic properties as described below.

Selected compounds of the present invention are also useful in thetreatment of depression in mammals, as demonstrated by their ability toinhibit tetrabenazine-induced depression in mice [International Journalof Neuropharmacology, 8 73 (1969)], a standard assay for usefulantidepressant properties. Thus, at an intraperitoneal dose of 20 mg/kg,2-methyl-1,2,3,4-tetrahydro-4-(m-trifluoromethylphenoxy)isoquinolinemaleate and 2-methyl-4-(p-nitrophenoxy)-1,2,3,4-tetrahydroisoquinolineeffect a 50% inhibition and a 30% inhibition, respectively, of theptosis of tetrabenazine-induced depression in mice. Amitriptyline, astandard compound for antidepression, exhibits a 50% inhibition of theptosis of tetrabenazine-induced depression in mice at an intraperitonealdose of 2 mg/kg.

Also indicative of the usefulness of selected compounds of the presentinvention as antidepressant in mammals, is their demonstration ofeffectiveness in L-5-hydroxytryptophan (5 HTP) potentiation in rats.

Groups of six male Wistar rats (150-200 grams) are used in this textprocedure. Four hours prior to testing pargyline HCl is prepared andadministered by subcutaneous injection at 75 mg/kg in 1% saline and at adosage volume of 1.25 ml/kg. Thirty minutes before testing, drugs areprepared using distilled water and, if insoluble, a suitable surfactantis added. Control groups receive vehicle. Drugs are routinelyadministered intraperitoneally (i.p.) at a dosage volume of 10 ml.kg.

L-5-Hydroxytryptophan is prepared at 1.0 mg/kg in distilled water and isadministered i.p. in volumes proportional to 10 ml/kg. Drugs areadministered in a randomized manner and 5-minute post 5-HTP treatmentthe animals are observed for 15 minutes.

A compound is considered to potentiate 5-HTP activity if the animalsexhibit continuous forelimb clonus. Potentiation is expressed asnormalized percent potentiation relative to vehicle control. When acompound is observed to potentiate 5-HTP activity, a dose range usingten animals per group is run in the same manner. An effective dose (ED)is determined by probit analysis.

Thus an intraperitoneal dose of 7.8 and 4.5 mg/kg, respectively, of2-methyl-1,2,3,4-tetrahydro-4-(m-trifluoromethylphenoxy)isoquinolinemaleate and 2-methyl-4-(p-nitrophenoxy)-1,2,3,4-tetrahydroisoquinolinerepresent ED₅₀ doses. The ED₅₀ of amitriptyline (standard) is 7.1.

The antidepressant effect is achieved when these compounds of theinvention are administered to a subject requiring such treatment at aneffective oral, parenteral or intravenous dose of from 1 to 100 mg/kg ofbody weight per day. A preferred effective dose within this range isfrom about 1 to 10 mg/kg of body weight per day.

Selected compounds of the present invention are useful as diuretics. Thediuretic activity of the compounds is measured in the following manner.

Groups of female Wistar rats (150-200 grams) are used and they are fooddeprived 16 hours prior to testing. Drugs are prepared in 1% saline andadministered in a dosage volume of 15 ml/kg orally. After dosing eachanimal is placed in an individual metabolic cage. Water is permitted adlibitum. Urine is collected from 0-5 hours after dosing.

Each test consists of a vehicle control, a positive control group ofurea treated (1000 mg/kg) and the potential diuretic agent (50 mg/kg)treated.

The individual urine samples are analyzed for sodium and/or potassiumand chloride. Sodium and potassium values are typically determined usinga flame photometer. Chloride determinations are typically made by achloride analyzer. Sodium, potassium and chloride values are expressedas the mean milliequivalents (mEq)/kg/5 hrs. Diuresis is expressed asthe mean milliliters (ml)/kg/5 hrs.

The mean values obtained for sodium, potassium, chloride and diuresisare expressed in a ratio to the sodium, potassium, chloride and diuresisvalues obtained for the urea treated group. This ratio is called the"drug to urea ratio." A drug to urea ratio greater than or equal to onefor diuresis and/or sodium is indicative of diuretic activity.

The diuretic effect of some of the compounds of the invention, expressedas the ratio of (a) the mean values obtained for diuresis (urine volume)of the compound treated group to the urea treated group and (b) the meanvalues obtained for sodium of the compound treated group to the ureatreated group, are given in Table I.

                  TABLE I                                                         ______________________________________                                                                   Diuresis                                                                      Drug     Sodium                                                      Dose     to Urea  Drug                                                        (oral)   Ratio    to Urea                                   COMPOUND          (mg/kg)  (Vol.)   Ratio                                     ______________________________________                                        4-(p-cyanophenoxy)-2-methyl-                                                                    50       1.1      1.2                                       1,2,3,4-tetrahydroisoquinoline                                                2-(2-N,N--dimethylaminoethyl)                                                                   25       1.1      1.4                                       1,2,3,4-tetrahydro-4-(p-trifluoro-                                            methylphenoxy)isoquinoline                                                    2-(2-N,N--diethylaminoethyl)-                                                                   25       1.4      1.0                                       1,2,3,4-tetrahydro-4-(p-tri-                                                  fluoromethylphenoxy)iso-                                                      quinoline dioxalate                                                           2-(3-piperidinopropyl)-1,                                                                       10       1.6      2.2                                       2,3,4-tetrahydro-4-(p-trifluoro-                                              methylphenoxy)isoquinoline                                                    dioxalate                                                                     ethacrynic acid   64       2.5                                                tienilic acid     64       1.8                                                ______________________________________                                    

The diuretic effect is achieved when these compounds of the inventionare administered to a subject requiring such treatment at an effectiveoral, parenteral or intravenous dose of from 1 to 100 mg/kg of bodyweight per day.

It is to be understood, however, that for any particular subject,specific dosage regimens for the above described diuretic,antidepressant, anticonvulsant and analgetic activity should be adjustedaccording to the individual need and the professional judgment of theperson administering or supervising the administration of the compoundsof the invention. It is to be further understood that the dosages setforth herein are examples only and that they do not, to any extent limitthe scope or practice of the invention.

Some examples of the invention are:

4-(o-methoxyphenoxy)-2-methyl-1,2,3,4-tetrahydroisoquinoline;

4-(o-cyanophenoxy)-2-methyl-1,2,3,4-tetrahydroisoquinoline;

6-methoxy-2-methyl-1,2,3,4-tetrahydro-4-(p-trifluoromethylphenoxy)isoquinoline;and

2-(3-piperidinopropyl)-1,2,3,4-tetrahydro-4-(p-trifluoromethylphenoxy)isoquinoline.

As indicated in the above-described preparation of the compounds of theinvention, compounds having the structural formula ##STR18## where R, Xand Y are as defined above, and R₄ is hydrogen, lower alkyl of 1 to 6carbon atoms and phenyl, are useful as intermediates for compounds ofthe invention having the structural formula ##STR19##

Some examples of intermediates are:

4-(p-cyanophenoxy)-2-ethoxycarbonyl-7-methoxy-1,2,3,4-tetrahydroisoquinoline;

4-(p-cyanophenoxy)-6,7-dimethoxy-2-ethoxycarbonyl-1,2,3,4-tetrahydroisoquinoline;

4-(p-benzoylphenoxy)-2-ethoxycarbonyl-1,2,3,4-tetrahydroisoquinoline;

2-ethoxycarbonyl-4-(p-phenylphenoxy)-1,2,3,4-tetrahydroisoquinoline;

2-ethoxycarbonyl-4-(p-methoxyphenoxy)-1,2,3,4-tetrahydroisoquinoline;and

2-ethoxycarbonyl-4-methyl-4-(p-nitrophenoxy)-1,2,3,4-tetrahydroisoquinoline

Effective amounts of the compounds of the present invention may beadministered to a subject by one of various methods, for example, orallyas in capsules or tablets, parenterally in the form of sterile solutionsor suspensions, and in some cases intravenously in the form of sterilesolutions. The compounds of the invention, while effective themselves,may be formulated and administered in the form of their pharmaceuticallyacceptable acid addition salts for purposes of stability, convenience ofcrystallization, increased solubility and the like.

Preferred pharmaceutically acceptable acid addition salts include thosederived from inorganic acids such as hydrochloric, hydrobromic,sulfuric, nitric, phosphoric, perchloric acids and the like as well asorganic acids such as tartaric, citric, acetic, succinic, maleic,fumaric acids and the like.

The compounds of the present invention may be administered orally, forexample, with an inert diluent or with an edible carrier. They may beenclosed in gelatin capsules or compressed into tablets. For the purposeof oral therapeutic administration, the compounds may be incorporatedwith excipients and used in the form of tablets, troches, capsules,elixirs, suspensions, syrups, wafers, chewing gums and the like. Theseprepartions should contain at least 4% of at least one compound of theinvention, the active ingredient, but may be varied depending upon theparticular form and may conveniently be between 4% to about 70% of theweight of the unit. The amount of the compound present in suchcompositions is such that a suitable dosage will be obtained. Preferredcompositions and preparations according to the present invention areprepared so that an oral dosage unit form contains between 5.0-300milligrams of the particular compound of the invention.

The tablets, pills, capsules, troches and the like may also contain thefollowing adjuvants: a binder such as microcrystalline cellulose, gumtragacanth or gelatin; an excipient such as starch or lactose; adisintegrating agent such as alginic acid, Primogel, cornstarch and thelike; a lubricant such as magnesium stearate or Sterotex; a glidant suchas colloidal silicon dioxide; and a sweetening agent such as sucrose orsaccharin may be added or a flavoring agent such as peppermint, methylsalicylate or orange flavoring. When the dosage unit form is a capsule,it may contain, in addition to materials of the above type, a liquidcarrier such as a fatty oil. Other dosage unit forms may contain othervarious materials which modify the physical form of the dosage unit, forexample, as coatings. Thus, tablets or pills may be coated with sugar,shellac, or other enteric coating agents. A syrup may contain, inaddition to the present compounds, sucrose as a sweetening agent andcertain preservatives, dyes and colorings and flavors. Materials used inpreparing these various compositions should be pharmaceutically pure andnon-toxic in the amounts used.

For the purpose of parenteral therapeutic administration, the compoundsof the present invention may be incorporated into a solution orsuspension. These preparations should contaIn at least 0.1% of thecompound of the invention, but may be varied to be between 0.1 and about50% of the weight thereof. The amount of the inventive compound presentin such compositions is such that a suitable dosage will be obtained.Preferred compositions and preparations according to the presentinvention are prepared so that a parenteral dosage unit contains between5.0 to 100 milligrams of the compound of the invention.

The solutions or suspensions may also include the following adjuvants; asterile diluent such as water for injection, saline solution, fixedoils, polyethylene glycols, glycerine, propylene glycol or othersynthetic solvents; antibacterial agents such as benzyl alcohol ormethyl paraben; antioxidants such as ascorbic acid or sodium bisulfite;chelating agents such as ethylene diaminetetraacetic acid; buffers suchas acetates, citrates or phosphates and agents for the adjustment oftonicity such as sodium chloride or dextrose. The parenteral preparationcan be enclosed in ampules, disposable syringes or multiple dose vialsmade of glass or plastic.

The following examples are for illustrative purposes and are not to beconstrued as limiting the invention disclosed herein. All temperaturesare given in degrees centigrade.

EXAMPLE 1 4-(o-Cyanophenoxy)-2-methyl-1,2,3,4-tetrahydroisoquinoline

A solution of 1,2,3,4-tetrahydro-2-methyl-4-isoquinolinol (5 g, 0.03mole) in dimethylformamide (DMF) (15 ml) is added dropwise undernitrogen to a stirred suspension of sodium hydride 50% (98%) (1.65 g,0.0337 mole) in freshly distilled DMF (25 ml). The mixture is warmed to70° C. for fifteen minutes, then cooled to about 40° C. A solution ofo-fluorobenzonitrile (3.71 g, 0.03 mole) in DMF (20 ml) is addeddropwise and stirred at room temperature for two hours. Addition ofwater yields a precipitate that is filtered and washed with water togive a solid which is dried over P₂ O₅ under vacuum to yield 6.2 g,78.2% of product. Recrystallization from methanol affords4-(o-cyanophenoxy)-2-methyl-1,2,3,4-tetrahydroisoquinoline, m.p.150°-151° C., 3.8 g (48%).

ANALYSIS: Calculated for C₁₇ H₁₆ N₂ O: 77.23% C, 6.11% H, 10.60% N.Found: 77.47% C, 6.20% H, 10.66% N. cl EXAMPLE 2

4-(p-Cyanophenoxy)-2-methyl-1,2,3,4-tetrahydroisoquinoline

A solution of 1,2,3,4-tetrahydro-2-methyl-4-isoquinolinol (3.0 g, 0.018mole) in dry DMF (15 ml) is added dropwise under nitrogen to asuspension of sodium hydride 50% (98%) (1.1 g, 0.022 mole), previouslywashed with hexane, in dry DMF (25 ml). The mixture is warmed to 60° C.,at which time a solution of 4-fluorobenzonitrile (2.2 g, 0.018 mole) indry DMF (15 ml) is slowly added. The reaction mixture is stirred at roomtemperature for 16 hours.

Most of the solvent is removed under reduced pressure and the resultantmixture is stirred in 500 ml water, then extracted with chloroform. Theorganic phase is washed twice with water, then dried (saturated NaCl,anhydrous MgSO₄). Removal of solvent yields a solid which is trituratedwith hexane then recrystallized from absolute ethanol to yield 3.3 g(68%) of a solid m.p. 131°-132° C. of4-(p-cyanophenoxy)-2-methyl-1,2,3,4-tetrahydroisoquinoline.

ANALYSIS: Calculated for C₁₇ H₁₆ N₂ O: 77.24% C, 6.10% H, 10.60% N.Found: 77.27% C, 6.10% H, 10.66% N.

EXAMPLE 3 4-(p-Benzoylphenoxy)-2-methyl-1,2,3,4-tetrahydroisoquinolineoxalate

A solution of 2-methyl-1,2,3,4-tetrahydro-4-isoquinolinol (3.0 g, 0.018mole) in dry DMF (15 ml) is added slowly to a suspension of NaH 50%(98%) (1.1 g, 0.022 mole), previously washed with hexane, in dry DMF (25ml). The mixture is warmed to 60° C., at which time a solution of4-fluorobenzophenone (3.7 g, 0.018 mole) in dry DMF (15 ml) is addeddropwise. The reaction mixture is allowed to stir at room temperaturefor 16 hours.

Most of the solvent is removed under reduced pressure and the resultantmixture is stirred in 500 ml water, the extracted with chloroform. Theorganic phase is washed twice with water, then dried (saturated NaCl,anhydrous MgSO₄). Removal of solvent yields an oil which is dissolved inether and converted to the oxalate salt by the addition of an etherealsolution of oxalic acid. Trituration with ethyl acetate or methanolyields 3.1 g (39%) of a solid of4-(p-benzoylphenoxy)-2-methyl-1,2,3,4-tetrahydroisoquinoline oxalate d @201° C.

ANALYSIS: Calculated for C₂₃ H₂₁ NO₂.(CO₂ H)₂ : 69.27% C, 5.35% H, 3.23%N. Found: 69.26% C, 5.39% H, 3.10% N.

EXAMPLE 44-(p-Trifluoromethylphenoxy)-2-methyl-1,2,3,4-tetrahydroisoquinolineoxalate

A solution of 2-methyl-1,2,3,4-tetrahydro-4-isoquinolinol (3.0 g, 0.018mole) in dry DMF (15 ml) is added slowly to a suspension of sodiumhydride 50% (98%) (1.1 g, 0.022 mole), previously washed with hexane, indry DMF (25 ml). After one hour p-fluorobenzotrifluoride (3.0 g, 0.018mole) in dry DMF (15 ml) is slowly added. The reaction mixture isallowed to stir at room temperature for about 16 hours. Most of thesolvent is removed under reduced pressure and the resultant mixture isstirred in 500 ml water, then extracted with chloroform. The organicphase is twice washed with water then dried (saturated NaCl, anhydrousMgSO₄). Removal of solvent yields an oil which is dissolved in ether andconverted to the oxalate salt as in Example 3. Recrystallization fromethylacetate-methanol (10:1) yields 4.6 g (64%) of a white solid of4-(p-trifluoromethylphenoxy)-2-methyl-1,2,3,4-tetrahydroisoquinolineoxalate d @ 183° C.

ANALYSIS: Calculated for C₁₇ H₁₆ F₃ NO.(CO₂ H)₂ : 57.43% C, 4.57% H,3.53% N. Found: 57.51% C, 4.70% H, 3.51% N.

EXAMPLE 54-(p-Cyanophenoxy)-2-ethoxycarbonyl-1,2,3,4-tetrahydroisoquinoline

To a solution of2-benzyl-4-(p-cyanophenoxy)-1,2,3,4-tetrahydroisoquinoline (4.5 g; 0.013mole) in CHCl₃ (50 ml) is added ethyl chloroformate (1.6 g, 0.014 mole).The mixture is allowed to reflux for two hours. The solvent is removedunder reduced pressure to yield an oil which, upon trituration withether, yields 3.1 g (73%) of a solid of4-(p-cyanophenoxy)-2-ethoxycarbonyl-1,2,3,4-tetrahydroisoquinoline, m.p.110° C.

ANALYSIS: Calculated for C₁₉ H₁₈ N₂ O₃ : 70.79% C, 5.63% H, 8.69% N.Found: 70.78% C, 5.58% H, 8.59% N.

EXAMPLE 6 4-(p-Phenylphenoxy)-2-methyl-1,2,3,4-tetrahydroisoquinolinehydrochloride

A solution of 1,2,3,4-tetrahydro-2-methyl-4-isoquinolinol (3.2 g, 0.020mole) in 20 ml of dry DMF is added dropwise under nitrogen to asuspension of sodium hydride 50% (98%) (1.1 g, 0.022 mole), previouslywashed with hexane, in 15 ml dry DMF. After one hour a solution ofp-fluorobiphenyl (3.4 g, 0.020 mole) in 20 ml dry DMF is added dropwise.The reaction mixture is allowed to stir at 65° C. for two hours.

Most of the solvent is removed under reduced pressure and the resultantmixture is stirred in 500 ml water, then extracted with chloroform. Theorganic phase is twice washed with water then dried (saturated NaCl,anhydrous MgSO₄). Removal of solvent yields 6 g of an oil which ispurified by dry column chromatography over silica gel using ethylacetate as the eluent. The desired product is crystallized from ether asthe hydrochloride salt, yielding 1.3 g (18%) of a solid of4-(p-phenylphenoxy-2-methyl-1,2,3,4-tetrahydroisoquinolinehydrochloride, m.p. 134° C.

ANALYSIS: Calculated for C₂₂ H₂₁ NO.HCl: 75.09% C, 6.30% H, 3.98% N.Found: 75.11% C, 6.34% H, 3.92% N.

EXAMPLE 7 4-(p-Chlorophenoxy)-2-methyl-1,2,3,4-tetrahydroisoquinolinehydrochloride

A solution of 1,2,3,4-tetrahydro-2-methyl-4-isoquinolinol (3.3 g, 0.020mole) in dry DMF is added dropwise under nitrogen to a suspension ofsodium hydride 50% (98%) (1.6 g, 0.033 mole), previously washed withhexane, in 40 ml dry DMF, at 65° C. After the evolution of gas ceases, asolution of p-chlorofluorobenzene (3.6 g, 0.028 mole) in 15 ml dry DMFis added slowly, and the resulting mixture is allowed to stir at 75° C.for 16 hours. After cooling to room temperature the solution is pouredinto water (110 ml), extracted with chloroform, the chloroform phase iswashed twice with water, dried (saturated NaCl, anhydrous MgSO₄) andremoved via reduced pressure to yield an oil which is purified by drycolumn chromatography, over silica gel using ethyl acetate as theeluent. The desired product is crystallized from ether as thehydrochloride salt, yielding 1.9 g (31%) of a solid of4-(p-chlorophenoxy)-2-methyl-1,2,3,4-tetrahydroisoquinolinehydrochloride, d @ 92° C.

ANALYSIS: Calculated for C₁₆ H₁₆ ClNO.HCl: 61.94% C, 5.52% H, 4.52% N.Found: 61.74% C, 5.45% H, 4.56% N.

EXAMPLE 8 2-Methyl-4-phenoxy-1,2,3,4-tetrahydroisoquinoline

A solution of 2-methyl-1,2,3,4-tetrahydro-4-isoquinolinol (6.0 g, 0.037mole) in 30 ml dry DMF is added dropwise under nitrogen to a suspensionof sodium hydride 50% (98%) (2.2 g, 0.044 mole), previously washed withhexane, in 50 ml dry DMF. After one hour the mixture is slowly warmed to75° C. at which time fluorobenzene (7.1 g. 0.074 mole) in 30 ml dry DMFis added dropwise. The reaction mixture is stirred at 95° C. for fourhours then at 75° C. for about 16 hours. Most of the solvent is removedunder reduced pressure and the resultant mixture is stirred in 500 mlwater then extracted with chloroform. The combined organic extracts arewashed twice with water and then dried (saturated NaCl, anhydrousMgSO₄). Removal of solvent yields 5.8 g (65%) of an oil which ispurified by dry column chromatography over silica gel using ethylacetate as the eluent. The desired product is extracted with chloroformto yield 1.5 g (17%) of an oil of2-methyl-4-phenoxy-1,2,3,4-tetrahydroisoquinoline.

ANALYSIS: Calculated for C₁₆ H₁₇ NO: 80.30% C, 7.16% H, 5.85% N. Found:80.07% C, 7.22% H, 5.79% N.

EXAMPLE 96,7-Dimethoxy-2-methyl-1,2,3,4-tetrahydro-4-(p-trifluoromethylphenoxy)-isoquinolinehydrochloride

To a suspension of NaH (50% in oil, 1.1 g, 0.023 mole) in 10 ml DMF, isadded a solution of6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydro-4-isoquinolinol (4.2 g, 0.019mole) in 25 ml DMF. The mixture becomes warm with gas evolution, and isstirred for one hour at ambient temperature. To this is added a solutionof p-(trifluoromethyl)fluorobenzene (3.1 g, 0.019 mole) in 20 ml DMF,and the mixture is stirred at ambient temperature for twenty-four hours.

The mixture is evaporated to a semi-solid, which is stirred with 500 mlwater for thirty minutes, then extracted with chloroform. The chloroformlayer is washed twice with water, then dried (saturated NaCl, anhydrousMgSO₄). After filtering, the solvent is evaporated to an oil which isdissolved in ether, then converted to a hydrochloride salt by theaddition of ethereal hydrogen chloride to yield 5.8 g (75%), d @ 95° C.This material is recrystallized twice from ethyl acetate/methanol (10:1)to yield 3.8 g of6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydro-4-(p-trifluoromethylphenoxy)isoquinolinehydrochloride, d @ 145° C.

ANALYSIS: Calculated for C₁₉ H₂₀ F₃ NO₃.HCl: 56.51% C, 5.24% H, 3.47% N.Found: 56.55% C, 5.58% H, 3.58% N.

EXAMPLE 104-(o-Cyanophenoxy)-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline

A solution of 6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydro-4-isoquinolinol(8.5 g, 0.038 mole) in dry DMF (40 ml) is added dropwise under nitrogento a suspension of sodium hydride 50% (98%) (2.3 g, 0.046 mole),previously washed with hexane, in dry DMF (30 ml). The mixture isstirred at room temperature for one hour at which time a solution ofo-fluorobenzonitrile (4.6 g, 0.038 mole) in dry DMF (30 ml) is slowlyadded. The reaction mixture is stirred at room temperature for aboutsixteen hours. The solvent is removed under reduced pressure and theresultant mixture is stirred in 500 ml water, then extracted withchloroform. The combined organic phases are washed twice with water thendried (saturated NaCl, anhydrous MgSO₄). Removal of solvent yields asolid (14.4 g, m.p. 120°-129° C.) which is twice recrystallized frommethanol to yield 8.4 g (68%) of4-(o-cyanophenoxy)-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline,m.p. 147°-148° C.

ANALYSIS: Calculated for C₁₉ H₂₀ N₂ O₃ : 70.35% C, 6.22% H, 8.64% N.Found: 70.14% C, 6.12% H, 8.54% N.

EXAMPLE 112-Ethoxycarbonyl-1,2,3,4-tetrahydro-4-(p-trifluoromethylphenoxy)isoquinoline

To a solution of2-methyl-1,2,3,4-tetrahydro-4-(p-trifluoromethylphenoxy)isoquinoline ofExample 4 (18.0 g, 0.06 mole) in 200 ml benzene, is added K₂ CO₃ (20 g,0.145 mole), and, with stirring, a solution of ethyl chloroformate (7.6g, 0.07 mole) in 50 ml benzene. After refluxing for four hours, themixture is cooled, washed twice with 100 ml portions of water, thricewith dilute HCl solution (100 ml), twice with water (100 ml), then dried(saturated NaCl, anhydrous MgSO₄). After filtering, the solvent isevaporated to an oil, which solidifies upon cooling, to a solid, 13.7 g(64%), m.p. 84° C. This material is recrystallized from hexanes twice,to yield 11.0 g, m.p. 107°-109° C. of2-ethoxycarbonyl-1,2,3,4-tetrahydro-4-(p-trifluoromethylphenoxy)isoquinoline.

ANALYSIS: Calculated for C₁₉ H₁₈ F₃ NO₃ : 62.46% C, 4.97% H, 3.83% N.Found: 62.59% C, 5.10% H, 3.84% N.

EXAMPLE 122-Methyl-1,2,3,4-tetrahydro-4-(m-trifluoromethylphenoxy)isoquinolinemaleate

To a suspension of NaH (50% in oil, 7.2 g, 0.15 mole) in 25 ml DMF, isadded a solution of 2-methyl-1,2,3,4-tetrahydro-4-isoquinolinol (20.0 g,0.123 mole) in 50 ml DMF in about thirty minutes. The mixture becomeswarm with a vigorous evolution of gas. After stirring at ambienttemperature for one hour, a solution of m-trifluoromethylfluorobenzene(24.6 g, 0.15 mole) in 50 ml DMF is added in about thirty minutes. Afterstirring at ambient temperature for twenty hours the reaction mixture isconcentrated to an oil which is poured into 500 ml water, and stirredfor 30 minutes. The resultant solution is extracted with chloroform andthe chloroform extract washed twice with water, then dried (saturatedNaCl, anhydrous MgSO₄). After filtering, the solvent is evaporated to anoil, which is dissolved in ether, and the HCl-salt precipitated by theaddition of ethereal hydrogen chloride. The salt is washed with ether,dissolved in water, neutralized with saturated Na₂ CO₃ solution, thenextracted with ether. The ether layer is washed twice with water thendried (saturated NaCl, anhydrous MgSO₄).

After filtering, the solvent is evaporated to an oil, which uponstanding in the cold solidifies to a solid, 26 g (69%) m.p. 50° C. Asample of this solid is converted to a maleate salt by the addition ofethereal maleic acid, and recrystallization twice from ethylacetate/ether (5:1) yields 4.0 g of2-methyl-1,2,3,4-tetrahydro-4-(m-trifluoromethylphenoxy)isoquinolinemaleate, m.p. 121°-123° C.

ANALYSIS: Calculated for C₁₇ H₁₆ F₃ NO.C₄ H₄ O₄ : 59.57% C, 4.76% H,3.31% N. Found: 59.73% C, 4.86% H, 3.41% N.

EXAMPLE 132-Ethoxycarbonyl-1,2,3,4-tetrahydro-4-(m-trifluoromethylphenoxy)isoquinoline

To 250 ml benzene, is added2-methyl-1,2,3,4-tetrahydro-4-(m-trifluoromethylphenoxy)isoquinoline(22.0 g, 0.072 mole) of Example 12, K₂ CO₃ (20.0 g, 0.145 mole), andethyl chloroformate (10.8 g, 0.1 mole).

After stirring at reflux for twenty-four hours, the mixture is cooled,washed twice with water, thrice with dilute HCl solution, twice withwater, then dried (saturated NaCl, anhydrous MgSO₄). After filtering thesolvent is evaporated to an oil, which solidified to a solid upontrituration with petroleum ether, to yield 18 g (70%) m.p. 94°-96° C. Asample of this material is recrystallized twice from hexanes, to yield asolid of2-ethoxycarbonyl-1,2,3,4-tetrahydro-4-(m-trifluoromethylphenoxy)isoquinoline,m.p. 98°-100° C.

ANALYSIS: Calculated for C₁₉ H₁₈ F₃ NO₃ : 62.46% C, 4.97% H, 3.83% N.Found: 62.61% C, 4.95% H, 3.87% N.

EXAMPLE 14 1,2,3,4-Tetrahydro-4-(p-trifluoromethylphenoxy)isoquinolinehydrochloride

A mixture of2-ethoxycarbonyl-1,2,3,4-tetrahydro-4-(p-trifluoromethylphenoxy)isoquinoline(21.7 g, 0.059 mole) of Example 13, KOH (25 g, 0.05 mole) and water (25ml) in 300 ml n-propanol is refluxed for 4.5 hours. After cooling, thesolvent is removed to yield an oil which is stirred in 500 ml water,then extracted with chloroform. The combined organic phases are washedtwice with water, then dried (saturated NaCl, anhydrous MgSO₄). Removalof solvent yields 15.4 g (89%) of a solid, of which 1.0 g is dissolvedin ether and converted to the hydrochloride salt (1.0 g, d @ 174°-187°C.) by the addition of ethereal hydrogen chloride. This material istwice recrystallized from ethyl acetate to yield 0.8 g (73%) of1,2,3,4-tetrahydro-4-(p-trifluoromethylphenoxy)isoquinolinehydrochloride, d @ 202° C.

ANALYSIS: Calculated for C₁₆ H₁₄ F₃ NO.HCl: 58.28% C, 4.59% H, 4.25% N.Found: 58.13% C, 4.88% H, 4.06% N.

EXAMPLE 152-(3-Dimethylaminopropyl)-1,2,3,4-tetrahydro-4-(p-trifluoromethylphenoxy)isoquinolinedihydrochloride

A mixture of 1,2,3,4-tetrahydro-4-(p-trifluoromethylphenoxy)isoquinolineof Example 14 (4.9 g, 0.017 mole), 3-dimethylaminopropyl chloride (2.5g, 0.021 mole), potassium carbonate (20 g) and KI (0.01 g) in 100 mln-butanol is refluxed for seven hours.

The reaction mixture is filtered and the solvent is removed to yield anoil which is stirred in 500 ml water then extracted with ether. Thecombined ether extracts are washed twice with water then dried(saturated NaCl, anhydrous MgSO₄). After filtering, the solvent isremoved to yield an oil which is dissolved in ether, then converted tothe dihydrochloride salt (5.8 g, 92%) by the addition of etherealhydrogen chloride.

This material is twice recrystallized from ethyl acetate-methanol (10:1)to yield 2.6 g (34%) of2-(3-dimethylaminopropyl)-1,2,3,4-tetrahydro-4-(p-trifluoromethylphenoxy)isoquinolinedihydrochloride.

ANALYSIS: Calculated for C₂₁ H₂₅ F₃ N₂ O.2HCl: 55.88% C, 6.03% H, 6.21%N. Found: 55.70% C, 6.13% H, 5.97% N.

EXAMPLE 164-(p-Chlorophenoxy)-2-ethoxycarbonyl-1,2,3,4-tetrahydroisoquinoline

A mixture of 4-(p-chlorophenoxy)-2-methyl-1,2,3,4-tetrahydroisoquinolineof Example 7, (22.1 g, 0.08 mole), ethyl chloroformate (10.9 g, 0.1mole) and K₂ CO₃ (22 g) in benzene (250 ml) is refluxed seven hours.

The reaction mixture is filtered, diluted with ether (400 ml), washedwith water, dilute HCl, again with water, then dried (saturated NaCl,anhydrous MgSO₄). After filtering, the solvent is removed to yield 21.5g of an oil, which upon trituration with petroleum ether yields 14.6 g(63% based on recovered starting material) of a solid, m.p. 62°-68° C.An analytical sample is twice recrystallized from hexanes to yield4-(p-chlorophenoxy)-2-ethoxycarbonyl-1,2,3,4-tetrahydroisoquinoline,m.p. 78.5°-79.5° C.

ANALYSIS: Calculated for C₁₈ H₁₈ ClNO₃ : 65.16% C, 5.47% H, 4.22% N.Found: 65.20% C, 5.48% H, 4.12% N.

EXAMPLE 17 4-(p-Chlorophenoxy)-1,2,3,4-tetrahydroquinoline hydrochloride

A mixture of 4-(p-chlorophenoxy-2-ethoxycarbonyl-1,2,3,4-tetrahydroisoquinoline of Example 16 (13.0 g, 0.04mole), KOH (14 g) and water (14 ml) in n-propanol (170 ml) is refluxedfor four hours. Removal of solvent under reduced pressure yields an oilwhich is stirred in water (500 ml) then extracted with ether. Thecombined organic extracts are washed with water, then dried (saturatedNaCl, anhydrous MgSO₄). After filtering, the solvent is removed to yield9.4 g (90%) of an oil of which 4.0 g is dissolved in ether and convertedto the hydrochloride salt (3.8 g, 83%, d @ 184°-188° C.) by the additionof ethereal hydrogen chloride. An analytical sample is twicerecrystallized from ethyl acetate/methanol (10:1) to yield4-(p-chlorophenoxy)-1,2,3,4-tetrahydroisoquinoline hydrochloride, d @199° C.

ANALYSIS: Calculated for C₁₅ H₁₄ ClNO.HCl: 60.82% C, 5.10% H, 4.73% N.Found: 60.96% C, 5.17% H, 4.72% N.

EXAMPLE 18 1,2,3,4-Tetrahydro-4-(m-trifluoromethylphenoxy)isoquinolinemaleate

To a solution of potassium hydroxide (14.0 g, 0.25 mole) in 14 ml water,is added a solution of2-ethoxycarbonyl-1,2,3,4-tetrahydro-4-(m-trifluoromethylphenoxy)isoquinolineof Example 13 (11.5 g, 0.0315 mole) in 170 ml n-propanol, and themixture is stirred at reflux for four hours. After cooling, the solventis evaporated to a semi-solid, which is stirred with 500 ml water forfifteen minutes, then extracted with ether. The ether extract is washedtwice with water, then dried (saturated NaCl, anhydrous MgSO₄).

After filtering twice, the solvent is evaporated to an oil, which isconverted to a maleate salt by the addition of an ethereal solution ofmaleic acid to yield 10.8 g (84%) m.p. 127°-129° C. A sample of this isrecrystallized twice from ethyl acetate/ether, (1:1) to yield1,2,3,4-tetrahydro-4-(m-trifluoromethylphenoxy)isoquinoline maleate,m.p. 128°-129° C.

ANALYSIS: Calculated for C₁₆ H₁₄ F₃ NO.C₄ H₄ O₄ : 58.68% C, 4.43% H,3.42% N. Found: 58.71% C, 4.46% H, 3.40% N.

EXAMPLE 192-(3-Dimethylaminopropyl)-1,2,3,4-tetrahydro-4-(m-trifluoromethylphenoxy)isoquinolinedimaleate

To 100 ml n-butanol is added1,2,3,4-tetrahydro-4-(m-trifluoromethylphenoxy)isoquinoline of Example18 (4.4 g, 0.016 mole), dimethylaminopropyl chloride (3.0 g, 0.027mole), K₂ CO₃ (20.0 g, 0.145 mole), and 0.01 g of KI.

After stirring at reflux for twenty hours, the mixture is cooled, andthe solvent evaporated to an oil, which is stirred with 500 ml water forfifteen minutes, then extracted with ether. The ether extract is washedtwice with water, then dried (saturated NaCl, anhydrous MgSO₄). Afterfiltering, the solvent is evaporated to an oil which is converted to adimaleate salt by the addition of an ethereal solution of maleic acid toyield 5.2 g (57%), m.p. 90° C. This material is recrystallized twicefrom ethyl acetate/methanol (10:1) to yield 3.0 g of2-(3-dimethylaminopropyl)-1,2,3,4-tetrahydro-4-(m-trifluoromethylphenoxy)isoquinolinedimaleate, m.p. 168°-170° C.

ANALYSIS: Calculated for C₂₁ H₂₅ F₃ N₂ O.2C₄ H₄ O₄ : 57.04% C, 5.45% H,4.59% N. Found: 57.05% C, 5.28% H, 4.52% N.

EXAMPLE 204-(p-Chlorophenoxy)-2-(3-dimethylaminopropyl)-1,2,3,4-tetrahydroisoquinolinedimaleate

To 100 ml n-butanol is added4-(p-chlorophenoxy)-1,2,3,4-tetrahydroisoquinoline of Example 7 (5.2 g,0.02 mole), dimethylaminopropyl chloride (5.0 g, 0.04 mole), K₂ CO₃(20.0 g, 0.145 mole), and 0.01 g of KI.

After stirring at reflux (120° C.) for twenty hours, the mixture iscooled, filtered, and the filtrate evaporated to an oil, which isstirred with 500 ml water for fifteen minutes, then extracted withether. The ether extract is washed thrice with water, then dried(saturated NaCl, anhydrous MgSO₄). After filtering, the solvent isevaporated to an oil, which is converted to a dimaleate salt by theaddition of an ethereal solution of maleic acid to yield4-(p-chlorophenoxy)-2-(3-dimethylaminopropyl)-1,2,3,4-tetrahydroisoquinolinedimaleate, 5.0 g, m.p. 169°-171° C.

ANALYSIS: Calculated for C₂₀ H₂₅ ClN₂ O.2C₄ H₄ O₄ : 58.28% C, 5.76% H,4.86% N. Found: 58.29% C, 5.91% H, 4.80% N.

EXAMPLE 21 A. 2,4-Dimethyl-1,2,3,4-tetrahydroisoquinoline-4-olhydrochloride

To a solution of methyl magnesium chloride (13.9 g, 0.19 mole) in THF(68 ml), cooled to 10° C., is added slowly2-methyl-2,3-dihydro-4(1H)-isoquinolone (20.0 g, 0.12 mole) in THF (80ml). After the addition is completed the reaction mixture is allowed towarm to room temperature. The reaction mixture is poured slowly into oneliter saturated NH₄ Cl and stirred, then extracted with ether. Thecombined ethereal extracts are washed twice with water then dried(saturated NaCl, anhydrous MgSO₄). After filtering, removal of solventyields 20.5 g (93%) of a liquid which solidifies on cooling. 4.0 g ofthis material is dissolved in ether and is then converted to thehydrochloride salt by the addition of ethereal hydrogen chloride toyield 4.7 g, 98%, m.p. 183°-187° C. An analytical sample is obtained bytwice recrystallizing a 1.0 g sample to yield a solid of2,4-dimethyl-1,2,3,4-tetrahydroisoquinoline-4-ol hydrochloride, d @189°-190° C.

ANALYSIS: Calculated for C₁₁ H₁₅ NO.HCl: 61.82% C, 7.55% H, 6.56% N.Found: 61.92% C, 7.48% H, 6.50% N.

B.2,4-Dimethyl-1,2,3,4-tetrahydro-4-(p-trifluoromethylphenoxy)isoquinoline

A solution of 2,4-dimethyl-1,2,3,4-tetrahydroisoquinolin-4-ol (16.6 g,0.093 mole) of Example 21A in dry DMF (50 ml) is added dropwise undernitrogen to a stirred suspension of sodium hydride 50% (98%) (5.5 g,0.11 mole), previously washed with hexane, in dry DMF (50 ml). After theaddition is completed the mixture is stirred at room temperature for onehour then is warmed to 70° C. for one hour, at which timep-fluorobenzotrifluoride (16.8 g, 0.10 mole) in DMF (30 ml) is addedslowly. The reaction mixture is then warmed to 100° C. for nine hours.Most of the solvent is removed under reduced pressure and the resultantmixture is stirred in water (500 ml), then extracted with chloroform.The combined organic extracts are washed twice with water then dried(saturated NaCl, anhydrous MgSO₄). Removal of solvent yields 15.6 g(52%) of an oil which is purified by dry column chromatography oversilica gel using ethyl acetate as the eluent. The desired product isextracted with chloroform to yield 7.7 g (26%) of an oil of which 3.4 gis dissolved in ether and is then converted to the hydrochloride salt bythe addition of ethereal hydrogen chloride to yield (3.7 g, 98%, m.p.125°-136° C.). An analytical sample is twice recrystallized from ethylacetate to yield2,4-dimethyl-1,2,3,4-tetrahydro-4-(p-trifluoromethylphenoxy)isoquinolinehydrochloride, m.p. 145°-145.5° C.

ANALYSIS: Calculated for C₁₈ H₁₈ F₃ NO.HCl: 60.42% C, 5.35% H, 3.92% N.Found: 60.17% C, 5.43% H, 3.93% N.

EXAMPLE 22 4-(o-Methoxyphenoxy)-2-methyl-1,2,3,4-tetrahydroisoquinolinehydrochloride

A solution of 2-methyl-1,2,3,4-tetrahydro-4-isoquinolinol (11.4 g, 0.070mole) in 40 ml DMF is added dropwise under nitrogen to a suspension ofNaH 50% (98%) (4.1 g 0.084 mole), previously washed with hexane, in 20ml DMF. After one hour 2-fluoroanisole (11.5 g, 0.091 mole) in 40 ml DMFis added dropwise. The reaction mixture is stirred at 130°-135° foreight hours. Most of the solvent is removed under reduced pressure andthe resultant oil is stirred in 500 ml water, then extracted with ether.The combined organic extracts are washed twice with water then dried(saturated NaCl, anhydrous MgSO₄). Removal of solvent yields 12.4 g ofan oil which is purified by dry column chromatography over silica gelusing ethyl acetate as the eluent. The desired product is extracted withchloroform to yield 2.7 g (14%) of a solid which is dissolved in ether,then converted to the hydrochloride salt of 4-(o-methoxyphenoxy)-2-methyl-1,2,3,4-tetrahydroisoquinoline hydrochloride by the addition ofethereal hydrogen chloride (2.2 g, m.p. 79°-81° C.).

ANALYSIS: Calculated for C₁₇ H₁₉ NO₂.HCl: 66.77% C, 6.59% H, 4.58% N.Found: 66.26% C, 6.59% H, 4.65% N.

EXAMPLE 23 2-Methyl-4-(p-nitrophenoxy)-1,2,3,4-tetrahydroisoquinoline

A solution of 2-methyl-1,2,3,4-tetrahydro-4-isoquinolinol (5.0 g, 0.031mole) in dry DMF (30 ml) is added dropwise under nitrogen to a stirredsuspension of sodium hydride 50% (98%) (1.8 g, 0.037 mole), previouslywashed with hexane, in dry DMF (10 ml). After the addition is completedthe mixture is warmed to 60° C. for one hour, then cooled to 0°-5° C.with an ice bath. A solution of 1-fluoro-4-nitrobenzene (5.6 g, 0.040mole) in DMF (20 ml) is then slowly added at a rate such that thereaction mixture temperature does not exceed 10° C. After the additionis complete the reaction mixture is allowed to warm to room temperaturefor two hours.

The solvent is removed under reduced pressure and the resultant mixtureis stirred in water (400 ml), then extracted with chloroform. Thecombined organic phases are washed with water, then dried (saturatedNaCl, anhydrous MgSO₄). After filtering, the solvent is removed to yielda solid which is triturated with hexane to yield 8.5 g (97%), m.p.125°-133° C. An analytical sample is twice recrystallized from absoluteethanol to yield2-methyl-4-(p-nitrophenoxy)-1,2,3,4-tetrahydroisoquinoline, m.p.141.5°-143° C.

ANALYSIS: Calculated for C₁₆ H₁₆ N₂ O₃ : 67.59% C, 5.67% H, 9.86% N.Found: 67.40% C, 5.55% H, 9.93% N.

EXAMPLE 242-Ethoxycarbonyl-4-(p-nitrophenoxy)-1,2,3,4-tetrahydroisoquinoline

A mixture of 2-methyl-4-(p-nitrophenoxy)-1,2,3,4-tetrahydroisoquinolineof Example 23 (6.0 g, 0.021 mole), ethyl chloroformate (2.9 g, 0.026mole) and potassium carbonate (10 g) in benzene (100 ml) is refluxed forfour hours. The reaction mixture is diluted with ether, washed withwater, dilute HCl, again with water, then dried (saturated NaCl,anhydrous MgSO₄). An analytical sample is twice recrystallized fromhexanes/acetone (10:1) to yield2-ethoxycarbonyl-4-(p-nitrophenoxy)-1,2,3,4-tetrahydroisoquinoline, m.p.118°-119° C.

ANALYSIS: Calculated for C₁₈ H₁₈ N₂ O₅ : 63.15% C, 5.30% H, 8.18% N,Found: 63.37% C, 5.31% H, 8.25% N.

EXAMPLE 252,4-Dimethyl-4-(p-nitrophenoxy)-1,2,3,4-tetrahydroisoquinolinehydrochloride

A solution of 2,4-dimethyl-1,2,3,4-tetrahydro-4-isoquinolinol (10.0 g,0.056 mole) in dry DMF (50 ml) is added dropwise under nitrogen to astirred suspension of sodium hydride 50% (98%) (3.3 g, 0.068 mole),previously washed with hexanes, in dry DMF (20 ml). After the additionis completed the mixture is warmed at 65° C. for two hours to insuresalt formation, then cooled to 5° C. with an ice bath. A solution of1-fluoro-4-nitrobenzene (9.2 g, 0.065 mole ) in DMF (20 ml) is thenslowly added dropwise. The reaction mixture is warmed at 70° C. for fourhours. The solvent is removed under reduced pressure and the resultantmixture is stirred with water, then extracted with chloroform. Thecombined organic phases are washed twice with water, then dried(saturated NaCl, anhydrous MgSO₄). The solution is filtered, thenconcentrated to an oil which is dissolved in ether, then converted tothe hydrochloride salt by the addition of ethereal hydrogen chloride toyield (18.6 g, 94%, m.p. 82°-90° C.). A 5.5 g sample is twicerecrystallized from ethyl acetate/methanol (5:1) to yield2,4-dimethyl-4-(p-nitrophenoxy)-1,2,3,4-tetrahydroisoquinolinehydrochloride (2.7 g, m.p. 131°-132° C.).

ANALYSIS: Calculated for C₁₇ H₁₈ N₂ O₃.HCl: 60.98% C, 5.72% H, 8.37% N.Found: 61.23% C, 5.88% H, 8.49% N.

EXAMPLE 262-Phenoxycarbonyl-1,2,3,4-tetrahydro-4-(p-trifluoromethylphenoxy)isoquinoline

To a cold solution of2-methyl-1,2,3,4-tetrahydro-4-(p-trifluoromethylphenoxy)isoquinoline ofExample 4 (23 g, 0.075 mole) in 150 ml dichloromethane, is added 25 g K₂CO₃, followed by a solution of phenyl chloroformate (15.6 g, 0.1 mole)in 100 ml dichloromethane. After stirring at ambient temperature fortwenty hours, the mixture is filtered, and the solvent evaporated to anoil, which solidifies to a solid upon trituration with hexanes, 24 g(80%), m.p. 72° C. A sample of this material is recrystallized twicefrom hexanes, to yield2-phenoxycarbonyl-1,2,3,4-tetrahydro-4-(p-trifluoromethylphenoxy)isoquinoline,m.p. 101°-3° C.

ANALYSIS: Calculated for C₂₃ H₁₈ F₃ NO₃ : 66.82% C, 4.39% H, 3.39% N.Found: 67.18% C, 4.47% H, 3.30% N.

EXAMPLE 272-(2-N,N-Dimethylaminoethyl)-4-(p-trifluoromethylphenoxy)-1,2,3,4-tetrahydroisoquinolinedihydrochloride

A mixture of 1,2,3,4-tetrahydro-4-(p-trifluoromethylphenoxy)isoquinolineof Example 8 (5.0 g, 0.017 mole), 2-dimethylaminoethyl chloride (3.7 g,0.034 mole), K₂ CO₃ (10 g) and 0.01 g. of KI in n-butanol (100 ml) isrefluxed for two hours.

The mixture is cooled, filtered, then concentrated to an oil which isstirred with water then extracted with ether. The combined etherextracts are washed twice with water then dried (saturated NaCl,anhydrous MgSO₄).

The solution is filtered then concentrated to an oil (4.0 g) which isdissolved in ether and then converted to the dihydrochloride salt (3.6 ggummy solid, 49%) by the addition of ethereal hydrogen chloride. Thismaterial is twice recrystallized from ethyl acetate/methanol (10:1) toyield2-(2-N,N-dimethylaminoethyl)-4-(p-trifluoromethylphenoxy)-1,2,3,4-tetrahydroisoquinolinedihydrochloride (1.7 g, d @ 194°-195° C.).

ANALYSIS: Calculated for C₂₀ H₂₃ F₃ N₂ O.2HCl: 54.92% C, 5.76% H, 6.41%N. Found: 54.99% C, 5.95% H, 6.32% N.

EXAMPLE 282-(2-N,N-Diethylaminoethyl)-4-(p-trifluoromethylphenoxy)-1,2,3,4-tetrahydroisoquinolinedioxalate

A mixture of 1,2,3,4-tetrahydro-4-(p-trifluoromethylphenoxy)isoquinolineof Example 8 (5.0 g, 0.017 mole), 2-diethylaminoethyl chloride (4.6 g,0.034 mole), K₂ CO₃ (10 g) and 0.01 g. KI in n-butanol (100 ml) isrefluxed for 2.5 hours.

Removal of solvent yields an oil which is stirred with water thenextracted with ether. The combined ether extracts are washed twice withwater then dried (saturated NaCl, anhydrous MgSO₄). The solution isfiltered then concentrated to yield an oil (5.6 g) which is dissolved inether then converted to the dioxalate salt by the addition of anethereal solution of oxalic acid to yield 7.0 g, (72%) which decomposesat 152°-157° C. This material is twice recrystallized from ethylacetate/methanol (10:1) to yield2-(2-N,N-diethylaminoethyl)-4-(p-trifluoromethylphenoxy)-1,2,3,4-tetrahydroisoquinolinedioxalate (5.4 g, d @ 159°-160° C.).

ANALYSIS: Calculated for C₂₂ H₂₇ F₃ N₂ 0.2(CO₂ H)₂ : 54.54% C, 5.46% H,4.89% N. Found: 54.78% C, 5.43% H, 5.01% N.

EXAMPLE 292-(3-Piperidinopropyl)-1,2,3,4-tetrahydro-4-(p-trifluoromethylphenoxy)isoquinolinedioxalate

To 100 ml n-butanol, is added1,2,3,4-tetrahydro-4-(p-trifluoromethylphenoxy)isoquinoline of Example 8(5.0 g, 0.017 mole), 3-piperidinopropyl chloride (5.1 g, 0.03 mole), K₂CO₃ (10 g), and 0.01 g. of KI.

After refluxing at 120° C. for three hours, the mixture is cooled,filtered and then n-butanol evaporated to yield an oil. The oil isstirred with 300 ml water for ten minutes, then extracted thrice withether (100 ml). The ether extract is washed with water (100 ml), thendried (saturated NaCl, anhydrous MgSO₄).

After filtering, the ether is evaporated to an oil, which is convertedto a dioxalate salt by the addition of an ethereal solution of oxalicacid to yield 5.4 g (55%), m.p. 80° C. dec. This material isrecrystallized twice from ethyl acetate to yield2-(3-piperidinopropyl)-1,2,3,4-tetrahydro-4-(p-trifluoromethylphenoxy)isoquinolinedioxalate.

ANALYSIS: Calculated for C₂₄ H₂₉ F₃ N₂ O.2(CO₂ H)₂ : 56.18% C, 5.56% H,4.68% N. Found: 56.71% C, 5.55% H, 4.81% N.

EXAMPLE 304-(p-Chlorophenoxy)-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline

To a suspension of NaH (50% in oil, treated with hexanes, 7.2 g, 0.15mole), in 50 ml dry DMF is added a solution of6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydro-4-isoquinolinol (25.2 g, 0.113mole) in 75 ml dry DMF. (The mixture becomes warm with evolution ofgas.)

After stirring the mixture at 60° C. for one hour, it is cooled, then asolution of 4-chlorofluorobenzene (15.7 g, 0.12 mole) in 50 ml DMF isadded, and the resultant mixture is stirred at 100° C. for seven hours.

The mixture is cooled, evaporated to an oil, stirred with 400 ml waterfor fifteen minutes, then extracted with chloroform. The chloroformlayer is washed twice with water, then dried (saturated NaCl, anhydrousMgSO₄).

After filtering, the solvent is evaporated to an oil, which solidifiesto a solid upon trituration with petroleum ether, 30.1 g, (80%), m.p.107°-9° C. A sample of this material is recrystallized twice fromether/petroleum ether (1:5) to yield4-(p-chlorophenoxy)-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline,m.p. 112°-15° C.

ANALYSIS: Calculated for C₁₈ H₂₀ ClNO₃ : 64.76% C, 6.04% H, 4.20% N.Found: 64.81% C, 6.14% H, 4.10% N.

EXAMPLE 31 4-(p-Nitrophenoxy)-1,2,3,4-tetrahydroisoquinoline maleate

4-Hydroxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (6.7 g, 0.036mole) is slowly added to a stirred suspension of sodium hydride (3.9 g,0.079 mole), previously washed with hexanes, in dry DMF (65 ml). Thereaction mixture is maintained at 0°-5° C. during the addition and thenis slowly warmed to room temperature. After one hour the mixture isagain cooled and a solution of 1-fluoro-4-nitrobenzene (5.6 g, 0.040mole) in DMF (10 ml) is slowly added. The reaction mixture is stirred atroom temperature for about 16 hours then is poured over ice water andextracted with dichloromethane. The combined organic extracts are washedwith water then dried (saturated NaCl, anhydrous MgSO₄). The solution isfiltered then concentrated to a semi-solid which is dissolved inmethanol/ether, then converted to the maleate salt by the addition of anethereal solution of maleic acid to yield 8.5 g, (61%) d @ 164° C. Thismaterial is twice recrystallized from ethyl acetate/methanol (5:1) toyield 4-(p-nitrophenoxy)-1,2,3,4-tetrahydroisoquinoline maleate, d165°-166° C.

ANALYSIS: Calculated for C₁₅ H₁₄ N₂ O₃.C₄ H₄ O₄ : 59.06% C, 4.70% H,7.25% N. Found: 58.84% C, 4.71% H, 7.17% N.

EXAMPLE 322-(3-N,N-Dimethylaminopropyl)-4-(p-nitrophenoxy)-1,2,3,4-tetrahydroisoquinolinedihydrochloride

A mixture of 4-(p-nitrophenoxy)-1,2,3,4-tetrahydroisoquinoline ofExample 31 (5.0 g, 0.018 mole), 3-dimethylaminopropyl chloride (4.5 g,0.037 mole) and potassium carbonate (8.0 g) in n-butanol (100 ml) isrefluxed for three hours. The mixture is cooled, filtered, thenconcentrated to an oil which is stirred with water then extracted withdichloromethane. The combined organic extracts are washed twice withwater then dried (saturated NaCl, anhydrous MgSO₄). The solution isfiltered and then concentrated to an oil (5.5 g) which is dissolved inmethanol/ether and then converted to the dihydrochloride salt by theaddition of ethereal hydrogen chloride. This material is immediatelyrecrystallized from ethyl acetate/methanol (5:1) to yield2-(3-N,N-dimethylaminopropyl)-4-(p-nitrophenoxy)-1,2,3,4-tetrahydroisoquinolinedihydrochloride (2.3 g, m.p. 188°-189° C.).

ANALYSIS: Calculated for C₂₀ H₂₅ N₃ O₃.2HCl: 56.08% C, 6.35% H, 9.81% N.Found: 56.22% C, 6.70% H, 9.76% N.

What we claim is:
 1. A method of alleviating convulsions in a mammalwhich comprises administering to a mammal an anticonvulsant effectiveamount of a compound having the formula ##STR20## where Y is hydrogenand alkoxy of 1 to 6 carbon atoms; X is hydrogen, cyano, benzoyl,trifluoromethyl, phenyl, halogen, alkyl of 1 to 6 carbon atoms, alkoxyof 1 to 6 carbon atoms and nitro; R is hydrogen and alkyl of 1 to 6carbon atoms; R₁ is hydrogen, alkyl of 1 to 6 carbon atoms, aralkylwhere the alkyl moiety has 1 to 6 carbon atoms and ##STR21## where R₂and R₃ are the same of different and are hydrogen and alkyl of 1 to 6carbon atoms or R₂ and R₃ are fused together to form a pyrrolidino or apiperidino ring substituent; m is an integer of 1 or 2; n is an integerof 2 or 3 and a pharmaceutically acceptable acid addition salt thereof.2. A method of alleviating pain in a mammal which comprisesadministering to the mammal a pain alleviating effective amount of acompound having the formula ##STR22## wherein Y is hydrogen and alkoxyof 1 to 6 carbon atoms; X is hydrogen, cyano, benzoyl, trifluoromethyl,phenyl, halogen, aralkyl, where the alkyl moiety has 1 to 6 carbonatoms, alkoxy of 1 to 6 carbon atoms and nitro, R is hydrogen and alkylof 1 to 6 carbon atoms, R₁ is hydrogen, alkyl, of 1 to 6 carbon atoms,aralkyl where the alkyl moiety has 1 to 6 carbon atoms and ##STR23##where R₂ and R₃ are the same or different and are hydrogen and alkyl of1 to 6 carbon atoms or R₂ and R₃ are fused together to form apyrrolidino or a piperidino ring substituent; m is an integer of 1 or 2;n is an integer of 2 or 3; and a pharmaceutically acceptable acidaddition salt thereof.